Urinary tract infections, including cystitis and pyelonephritis, are among the most common of infectious diseases acquired by humans. These infections are responsible for substantial morbidity, mortality and high medical costs worldwide. An especially troublesome aspect of these infections is their strong tendency to recur. The vast majority of urinary tract infections are caused by strains of uropathogenic Escherichia coil (UPEC) that can bind and invade bladder epithelial cells. Within bladder cells, UPEC will either multiply or enter a non-replicating, persistent quiescent state that may serve as a reservoir for future recurrent acute infections. Intracellular UPEC is protected against standard antibiotic treatments that can effectively sterilize the urine. In addition, resistance to multiple antibiotics among UPEC isolates is becoming increasingly widespread, further limiting the efficacy of current treatment protocols for urinary tract infections. Using a cell culture model system, we recently found that inhibitors of the host transcription factor NF-kappaB are able to effectively interfere with the ability of UPEC to invade bladder epithelial cells, multiply intracellularly and reemerge from the host cells. NF-kappaB regulates the transcription of a number of host genes, including many associated with pro-inflammatory responses that work to limit infections. Our preliminary data, however, suggest the counterintuitive possibility that NF-kappaB activity is required for UPEC to effectively colonize and persist within host bladder epithelial cells. The primary Aim of this R21 application is to define the role of NF-kappaB as a regulator and potential facilitator of UPEC pathogenesis. In addition, we will test the therapeutic potential of a NF-kappaB inhibitor in the treatment and prevention of both acute and recurrent bladder infections using a well-established mouse cystitis model.